Research Proposal Description: Inhalation of fine particulate matter (PM) by humans and experimental animals results in increased microvascular permeability, pulmonary edema and in some instances, damage to epithelial cells. These changes are associated with an accumulation of macrophages in the tissue. Although numerous epidemiologic studies have demonstrated that fine particulate matter induces morbidity and mortality, the mechanisms underlying the toxic effects of these materials are unknown. It is the overall objective of this proposal to analyze the role of particle-associated peroxides and inflammatory macrophages in fine particulate matter-induced tissue injury. We hypothesize that fine particulate matter transports peroxides into the lower lungs leading to tissue injury and the accumulation and activation of macrophages in these regions. Once activated the macrophages release cytotoxic mediators and pro-inflammatory cytokines that contribute to the pathogenesis of tissue injury. To test this hypothesis studies are planned to 1) determine if lung injury induced by aerosols is mediated by cytotoxic peroxides carried into the lower airways by fine particulates; 2) determine if treatment of rats with fine particulate matter leads to activation of macrophages in the lung and to 3) evaluate the effects of modifying macrophage activity and mediator production on fine particulate matter-induced lung injury. For these studies rats will be exposed to ammonium sulfate aerosols with and without hydrogen peroxide. Measurements will be made tissue injury, macrophage accumulation and inflammatory mediator production using techniques in immunohistochemistry, in situ hybridization and electron microscopy. By pre-treating rats with various inhibitors of macrophages and inflammatory mediators we will be able to determine the relative contribution of these cells and cytotoxic products they release to injury. The results of our studies will provide important mechanistic information useful for designing new therapeutic approaches to treating toxicant-induced lung damage.